Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors

Abstract

This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating disorders mediated by cyclooxygenase-2 or 5-lipoxygenase, such as inflammation.

1. A compound or a pharmaceutically acceptable salt of the compound, wherein:
 the compound corresponds in structure to Formula I:                  
 
 A is pyrazolyl optionally substituted with a radical selected from the group consisting of acyl, halo, alkyl, haloalkyl, cyano, nitro, carboxyl, alkoxy, oxo, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, and hydroxyalkyl; 
 Y is selected from the group consisting of oxy, thio, sulfinyl, sulfonyl, alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkyloxyalkyl, hydroxyalkylthio, hydroxyalkylthioalkyl, oximinoalkoxy, oximinoalkoxyalkyl, (alkyl)oximinoalkoxy, (alkyl)oximinoalkoxyalkyl, oximinoalkylthio, oximinoalkylthioalkyl, (alkyl)oximinoalkylthio, (alkyl)oximinoalkylthioalkyl, carbonylalkyloxy, carbonylalkyloxyalkyl, carbonylalkylthio, carbonylalkylthioalkyl, cycloalkenyl, aralkyl, acyl, alkylthioalkyl, alkyloxyalkyl, alkenylthio, alkynylthio, alkenyloxy, alkynyloxy, alkenylthioalkyl, alkynylthioalkyl, alkenyloxyalkyl, alkynyloxyalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, haloalkylcarbonyl, alkoxyalkyl, alkylaminocarbonylalkyl, arylthioalkyl, aryloxyalkyl, haloaryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonylcyanoalkenyl, aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, cycloalkylaminocarbonyl, carboxyalkylaminocarbonyl, alkylcarbonylalkyl, aralkoxycarbonylalkylaminocarbonyl, haloaralkyl, carboxyhaloalkyl, alkoxycarbonylhaloalkyl, aminocarbonylhaloalkyl, alkylaminocarbonylhaloalkyl, N-alkylamino, N,N-dialkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aminoalkoxy, aminoalkoxyalkyl, aminoalkylthio, aminoalkylthioalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylthio, cycloalkylalkylthio, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl,                  
 
 Ar is aryl optionally substituted with one or two substituents selected from the group consisting of halo, hydroxyl, amino, nitro, cyano, carbamoyl, alkyl, alkenyloxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, haloalkyl, alkoxycarbonyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkanoylamino, cyanoalkoxy, carbamoylalkoxy, and alkoxycarbonylalkoxy, and                  
 
 R 1  is one or more substituents selected from the group consisting of cycloalkyl, cycloalkenyl, and aryl, wherein:
 any such substituent is optionally substituted with one or more radicals selected from the group consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio; 
 
 R 2  is selected from the group consisting of alkyl and amino; 
 R 3 , R 4 , and the carbon atom to which R 3  and R 4  are attached together form tetrahydropyranyl optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, alkyl, alkoxy, alkenyloxy, and alkynyloxy; 
 R 5  is selected from the group consisting of hydroxyl, alkoxy, alkylcarbonyloxy, and arylcarbonyloxy; 
 R 6  is selected from the group consisting of hydrido, alkyl, aryl, and aralkyl; 
 R 7  is selected from the group consisting of alkyl, alkenyl, and alkynyl; 
 R 8  is oximino optionally substituted with alkyl; and 
 n is zero or 1. 
 
     
     
       2. A compound or salt of  claim 1 , wherein:
 A is pyrazolyl optionally substituted with a radical selected from the group consisting of acyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl, 
 Y is selected from the group consisting of oxy, thio, sulfinyl, sulfonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower hydroxyalkyl, lower hydroxyalkyloxy, lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, lower oximinoalkoxyalkyl, lower (alkyl) oximinoalkoxy, lower (alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, lower carbonylalkyloxyalkyl, lower hydroxyalkylthio, lower hydroxyalkylthioalkyl, lower oximinoalkylthio, lower oximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower (alkyl)oximinoalkylthioalkyl, lower carbonylalkylthio, lower carbonylalkylthioalkyl, lower alkylthio, lower alkylcarbonyl, lower cycloalkyl, phenyl, lower haloalkyl, lower cycloalkenyl, lower aralkyl, acyl, lower alkylthioalkyl, lower alkyloxyalkyl, lower alkenylthio, lower alkynylthio, lower alkenyloxy, lower alkynyloxy, lower alkenylthioalkyl, lower alkynylthioalkyl, lower alkenyloxyalkyl, lower alkynyloxyalkyl, phenylcarbonyl, lower aralkylcarbonyl, lower aralkenyl, lower haloalkylcarbonyl, lower alkylaminocarbonylalkyl, lower arylthioalkyl, lower aryloxyalkyl, lower aralkylthioalkyl, lower aralkoxyalkyl, lower alkoxyaralkoxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonylcyanoalkenyl, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, N-phenylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl, lower alkylcarbonylalkyl, lower aralkoxycarbonylalkylaminocarbonyl, lower haloaralkyl, lower carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower N,N-dialkylamino, N-phenylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-aralkylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower N-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower aminoalkoxy, lower aminoalkoxyalkyl, lower aminoalkylthio, lower aminoalkylthioalkyl, lower cycloalkyloxy, lower cycloalkylalkyloxy, lower cycloalkylthio, lower cycloalkylalkylthio, phenyloxy, lower aralkoxy, phenylthio, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-alkylaminosulfonyl, lower N-arylaminosulfonyl, lower arylsulfonyl, lower N,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl,                  
 
 Ar is selected from the group consisting of phenyl, biphenyl, and naphthyl, wherein:
 the phenyl, biphenyl, or naphthyl is optionally substituted with one or two substituents selected from the group consisting of halo, hydroxyl, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, lower haloalkyl, lower alkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl, lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, and lower alkoxycarbonylalkoxy, and                  
 
 
 R 1  is at least one substituent selected from the group consisting of lower cycloalkyl, lower cycloalkenyl, phenyl, biphenyl, and naphthyl, wherein:
 any such substituent is optionally substituted with one or more radicals selected from the group consisting of lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; 
 
 R 2  is selected from the group consisting of lower alkyl and amino; 
 R 3 , R 4 , and the carbon atom to which R 3  and R 4  are attached together form tetrahydropyranyl optionally substituted with up to, three substituents independently selected from the group consisting of hydroxyl, lower alkyl, lower alkoxy, lower alkenyloxy, and lower alkynyloxy; 
 R 5  is selected from the group consisting of hydroxyl, lower alkoxy, lower alkylcarbonyloxy, and phenylcarbonyloxy; 
 R 6  is selected from the group consisting of hydrido, lower alkyl, phenyl and lower aralkyl; 
 R 7  is selected from the group consisting of lower alkyl, lower alkenyl, and lower alkynyl; 
 R 8  is oximino optionally substituted with alkyl; and 
 n is zero or 1. 
 
     
     
       3. A compound or salt of  claim 2 , wherein:
 A is pyrazolyl optionally substituted with a radical selected from the group consisting of acyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; 
 Y is selected from the group consisting of oxy, thio, sulfinyl, sulfonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower hydroxyalkyl, lower hydroxyalkyloxy, lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, lower oximinoalkoxyalkyl, lower (alkyl) oximinoalkoxy, lower (alkyl) oximinoalkoxyalkyl, lower carbonylalkyloxy, lower carbonylalkyloxyalkyl, lower hydroxyalkylthio, lower hydroxyalkylthioalkyl, lower oximinoalkalkylthio, lower oximinoalkylthioalkyl, lower (alkyl) oximinoalkylthio, lower (alkyl) oximinoalkylthioalkyl, lower carbonylalkylthio, lower carbonylalkylthioalkyl, lower alkylthio, lower alkylcarbonyl, lower cycloalkyl, phenyl, lower haloalkyl, lower cycloalkenyl, lower aralkyl, acyl, lower alkylthioalkyl, lower alkyloxyalkyl, lower alkenylthio, lower alkynylthio, lower alkenyloxy, lower alkynyloxy, lower alkenylthioalkyl, lower alkynylthioalkyl, lower alkenyloxyalkyl, lower alkynyloxyalkyl, phenylcarbonyl, lower aralkylcarbonyl, lower aralkenyl, lower haloalkylcarbonyl, lower alkylaminocarbonylalkyl, lower arylthioalkyl, lower aryloxyalkyl, lower aralkylthioalkyl, lower aralkoxyalkyl, lower alkoxycarbonylalkyl, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, N-phenylaminocarbonyl, lower alkylcarbonylalkyl, lower N-alkylamino, N-phenylamino, lower N-aralkylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower aminoalkoxy, lower aminoalkoxyalkyl, lower aminoalkylthio, lower aminoalkylthioalkyl, lower cycloalkyloxy, lower cycloalkylalkyloxy, lower cycloalkylthio, lower cycloalkylalkylthio, phenyloxy, lower aralkoxy, phenylthio, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, oximino,                  
 
 Ar is selected from the group consisting of phenyl, biphenyl, and naphthyl, wherein:
 the phenyl, biphenyl, or naphthyl is optionally substituted with one or two substituents selected from the group consisting of halo, hydroxyl, amino, nitro, cyano, lower alkyl, lower alkoxy, and                  
 
 
 R 1  is at least one substituent selected from the group consisting of phenyl, biphenyl, and naphthyl, wherein:
 any such substituent is optionally substituted with one or more radicals selected from the group consisting of lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; 
 
 R 2  is selected from the group consisting of lower alkyl and amino; 
 R 3 , R 4 , and the carbon to which R 3  and R 4  are attached together form a tetrahydropyran ring optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, lower alkyl, and lower alkoxy; 
 R 5  is selected from the group consisting of hydroxyl and lower alkoxy; 
 R 6  is selected from the group consisting of hydrido, lower alkyl, phenyl and lower aralkyl; and 
 R 7  is selected from the group consisting of lower alkyl, lower alkenyl, and lower alkynyl. 
 
     
     
       4. A compound or salt of  claim 3 , wherein:
 A is pyrazolyl optionally substituted with a radical selected from the group consisting of acyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; 
 Y is selected from the group consisting of oxy, thio, sulfinyl, sulfonyl, lower alkyl, lower alkynyl, aryl, lower cycloalkyl, aralkyl, lower alkyloxy, aryloxy, arylthio, lower aralkylthio, lower aralkyloxy, lower alkylthio, lower alkynyloxy, lower alkynylthio, lower alkynyloxyalkyl, lower alkenyloxy, lower alkenylthio, lower alkenyloxyalkyl, lower alkyloxyalkyl, lower alkylthioalkyl, lower hydroxyalkyloxy, lower alkoxycarbonylalkyl, lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, lower oximinoalkoxyalkyl, lower (alkyl) oximinoalkoxy, lower (alkyl) oximinoalkoxyalkyl, lower carbonylalkyloxy, lower carbonylalkyloxyalkyl,                  
 
 Ar is phenyl optionally substituted with one or two substituents selected from the group consisting of halo, hydroxyl, lower alkyl, lower alkoxy, and                  
 
 R 1  is at least one substituent selected from the group consisting of cyclopentenyl and phenyl, wherein:
 any such substituent is optionally substituted with one or more radicals selected from the group consisting of lower alkyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, nitro, lower alkoxyalkyl, halo, lower alkoxy, and lower alkylthio; 
 
 R 2  is selected from the group consisting of lower alkyl and amino; 
 R 3 , R 4 , and the carbon to which R 3  and R 4  are attached together form a tetrahydropyran ring optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, lower alkyl, and lower alkoxy; 
 R 5  is selected from the group consisting of hydroxyl and lower alkoxy; 
 R 6  is selected from the group consisting of hydrido, and lower alkyl; and 
 R 7  is lower alkyl. 
 
     
     
       5. A compound or salt of  claim 4 , wherein:
 A is pyrazolyl optionally substituted with a radical selected from the group consisting of acyl, fluoro, chloro, bromo, methyl, trifluoromethyl, oxo, cyano, carboxyl, methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl, carboxypropyl, and hydroxymethyl; 
 Y is selected from the group consisting of oxy, ethyl, propyl, isopropyl, butyl, 1-propynyl, 2-propynyl, methyloxy, ethyloxy, propyloxy, methylthio, (Z)-1-propenyloxy, (E)-2-propenyloxy, (Z)-2-propenyloxy, (E)-1-propenyloxy, (Z)-1-propenyloxymethyl, (E)-2-propenyloxymethyl, (Z)-2-propenyloxymethyl, (E)-1-propenyloxymethyl, 1-propynyloxy, 2-propynyloxy, 1-propynylthio, 2-propynylthio, hydroxymethyloxy, 1-hydroxyethyloxy, 2-hydroxypropyloxy, hydroxymethyloxymethyl, 1-hydroxyethyloxymethyl, 2-hydroxypropyloxymethyl, methyloxymethyl, ethyloxymethyl, propyloxymethyl, 1-propynyloxymethyl, oximinomethyloxy, oximinomethyloxymethyl, (methyl)oximinomethyloxy, (methyl)oximinomethyloxymethyl, 1-(methoxymethyl)ethyl, methylthiomethyl, ethylthiomethyl, N-ethyl-N-methylaminocarbonylmethyloxy, N-ethyl-N-methylaminoethyloxy, carbonylmethyloxy, carbonylbutyloxy, and carbonylmethyloxymethyl; 
 Ar is phenyl optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, bromo, hydroxyl, methyl, methoxy, and                  
 
 R 1  is selected from the group consisting of phenyl optionally substituted with one or more radicals selected from the group consisting of methyl, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chloro, bromo, methoxy, and methylthio; 
 R 2  is methyl or amino; 
 R 3 , R 4 , and the carbon to which R 3  and R 4  are attached together form a tetrahydropyran ring optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, methyl, and methoxy; and 
 R 5  is selected from the group consisting of hydroxyl and methoxy. 
 
     
     
       6. A compound or salt of  claim 5 , wherein the compound is selected from the group consisting of:
 4-[5-(4-chlorophenyl)-3-(3-methoxyphenyl)oxymethyl-1H-pyrazol-1-yl]benzenesulfonamide; 
 4-[5-(4-chlorophenyl)-3-(3-methoxyphenyl)thiomethyl-1H-pyrazol-1-yl]benzenesulfonamide; 
 4-[5-(4-chlorophenyl)-3-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]-1H-pyrazol-1-yl]benzenesulfonamide; and 
 4-[5-(4-chlorophenyl)-3-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide. 
 
     
     
       7. A compound or pharmaceutically acceptable salt of the compound, wherein:
 the compound corresponds in structure to Formula II:                  
 
 A is a pyrazolyl optionally substituted with a radical selected from the group consisting of acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; 
 Y is selected from the group consisting of oxy, thio, sulfinyl, sulfonyl, lower alkyl, lower alkynyl, lower alkenyl, lower hydroxyalkyl, aryl, lower cycloalkyl, aralkyl, lower alkyloxy, aryloxy, arylthio, lower cycloalkyloxy, lower aralkylthio, lower aralkyloxy, lower alkylthio, lower alkynyloxy, lower alkynylthio, lower alkynyloxyalkyl, lower alkenyloxy, lower alkenylthio, lower alkenyloxyalkyl, lower alkyloxyalkyl, lower alkylthioalkyl, lower hydroxyalkylthio, lower hydroxyalkylthioalkyl, lower oximinoalkylthio, lower oximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower (alkyl)oximinoalkylthioalkyl, lower carbonylalkylthio, lower carbonylalkylthioalkyl, lower hydroxyalkyloxy, lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, lower oximinoalkoxyalkyl, lower (alkyl)oximinoalkoxy, lower (alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, and lower carbonylalkyloxyalkyl; 
 R 1  is a substituent selected from the group consisting of lower cycloalkyl, lower cycloalkenyl, phenyl, biphenyl, and naphthyl, wherein:
 any such substituent is optionally substituted with one or more radicals selected from the group consisting of lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; 
 
 R 2  is selected from the group consisting of lower alkyl and amino; 
 R 9  is one or two substituents selected from the group consisting of halo, hydroxyl, amino, nitro, cyano, carbamoyl, alkyl, alkenyloxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, haloalkyl, alkoxycarbonyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkanoylamino, cyanoalkoxy, carbamoylalkoxy, and alkoxycarbonylalkoxy; and 
 R 10  is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cyanoalkyl, alkanoyl, and benzoyl optionally substituted with a substituent selected from the group consisting of halo, alkyl and alkoxy. 
 
     
     
       8. A compound or salt of  claim 7 , wherein:
 A is pyrazolyl optionally substituted with a radical selected from the group consisting of acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; 
 Y is selected from the group consisting of oxy, lower alkyl, lower alkynyl, lower hydroxyalkyl, lower alkyloxy, lower alkylthio, lower alkyloxyalkyl, lower alkenyloxy, lower alkenyloxyalkyl, lower alkynyloxy, lower alkynylthio, lower alkynyloxyalkyl, lower alkylthioalkyl, lower hydroxyalkylthio, lower hydroxyalkylthioalkyl, lower oximinoalkylthio, lower oximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower (alkyl)oximinoalkylthioalkyl, lower carbonylalkylthio, lower carbonylalkylthioalkyl, lower hydroxyalkyloxy, lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, lower oximinoalkoxyalkyl, lower (alkyl)oximinoalkoxy, lower (alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, and lower carbonylalkyloxyalkyl; 
 R 1  is phenyl optionally substituted with one or more radicals selected from the group consisting of lower alkyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, halo, and lower alkoxy; 
 R 2  is selected from the group consisting of lower alkyl and amino; 
 R 9  is one or two substituents selected from the group consisting of halo, hydroxyl, amino, lower alkyl, lower alkoxy; and 
 R 10  is selected from the group consisting of hydrido and lower alkyl. 
 
     
     
       9. A compound or salt of  claim 8 , wherein:
 A is pyrazolyl optionally substituted with a radical selected from the group consisting of formyl, fluoro, chloro, bromo, hydroxyl, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, oxo, cyano, nitro, carboxyl, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, hexyloxy, methylenedioxy, aminocarbonyl, methoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, and hydroxymethyl; 
 Y is selected from the group consisting of oxy, ethyl, propyl, isopropyl, butyl, 1-propynyl, 2-propynyl, methyloxy, ethyloxy, propyloxy, methylthio, (Z)-1-propenyloxy, (e)-2-propenyloxy, (Z)-2-propenyloxy, (E)-1-propenyloxy, (Z)-1-propenyloxymethyl, (E)-2-propenyloxymethyl, (Z)-2-propenyloxymethyl, (E)-1-propenyloxymethyl, 1-propynyloxy, 2-propynyloxy, 1-propynylthio, 2-propynylthio, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethyloxy, 1-hydroxyethyloxy, 2-hydroxypropyloxy, hydroxymethyloxymethyl, 1-hydroxyethylxoymethyl, 2-hydroxypropyloxymethyl, methyloxymethyl, ethyloxymethyl, propyloxymethyl, 1-propynyloxymethyl, hydroxymethylthio, 1-hydroxyethylthio, 2-hydroxypropylthio, 1-hydroxyethylthio, 2-hydroxpropylthio, hydroxymethylthiomethyl, 1-hydroxyethylthiomethyl, 2-hydroxypropylthiomethyl, oximinomethylthio, oximinomethylthiomethyl, (methyl)oximinomethylthio, (methyl)oximinomethylthiomethyl, carbonylmethylthio, carbonylbutylthio, carbonylmethylthiomethyl, oximinomethyloxy, oximinomethyloxymethyl, (methyl)oximinomethyloxy, methylthiomethyl, (methyl)oximinomethyloxymethyl, ethylthiomethyl, 1-(methoxycarbonyl)ethyl, carbonylmethyloxy, carbonylbutyloxy, and carbonylmethyloxymethyl; 
 R 1  is phenyl optionally substituted with one or more radicals selected from the group consisting of methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, fluoro, dichloropropyl, hydroxyl, hydroxymethyl, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and hexyloxy; 
 R 2  is selected from the group consisting of methyl and amino; 
 R 9  is one or two substituents selected from the group consisting of fluoro, chloro, bromo, hydroxyl, amino, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and hexyloxy; and 
 R 10  is selected from the group consisting of hydrido and methyl. 
 
     
     
       10. A pharmaceutical composition comprising a therapeutically-effective amount of a compound or salt of  claim 1 . 
     
     
       11. A pharmaceutical composition comprising a therapeutically-effective amount of a compound or salt of  claim 7 .